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Chloroquine and Hydroxychloroquine Activity Against SARS-CoV-2: A Journal Club Review

Graber CJ. Chloroquine and Hydroxychloroquine Activity Against SARS-CoV-2: A Journal Club Review. Infectious Diseases Society of America (IDSA) Newsletter [Internet]. 2020 Apr 1. Available from: https://www.idsociety.org/idsa-newsletter/april-1-2020/chloroquine-and-hydroxychloroquine-activity-against-sars-cov-2--a-journal-club-review/.




Abstract:

The potential activity of chloroquine and hydroxychloroquine against SARS-CoV-2 has gained significant attention in the press, and their use in COVID-19 disease is being explored at many medical centers. However, the most convincing evidence for their use in COVID-19 disease is based on two cell culture studies. In a recently-published paper in Cell Research, investigators introduced varying concentrations of seven different agents to infected Vero E6 cells, then infected these cells with SARS-CoV-2 and measured viral copy numbers (via immunofluorescence) and cytotoxicity over a 48-hour time period. Remdesivir and chloroquine were the two agents that most potently blocked viral infection while not causing cytotoxicity across a wide range of concentrations. Subsequent time-of-addition assays demonstrated that chloroquine functioned at entry and post-entry stages of infection (while remdesivir's function was more at post-entry). Another recently-published paper in Clinical Infectious Diseases summarized in vitro antiviral activity of chloroquine and hydroxychloroquine with an eye toward developing optimized dosing for their potential use in COVID-19 disease. In a treatment study, Vero cells were infected with SARS-CoV-2 for 2 hours then treated with escalating doses of chloroquine and hydroxychloroquine. Both agents performed well (with somewhat lower inhibitory concentrations observed for hydroxychloroquine). In a pre-treatment study, Vero cells were pre-treated with chloroquine and hydroxychloroquine for 2 hours, then virus was added. In this experiment, hydroxychloroquine performed much better, though inhibitory concentrations tended to decrease for both with longer incubation times. Pharmacokinetic models were then used to predict lung tissue concentrations using one dosing regimen of chloroquine and five dosing regimens of hydroxychloroquine. The regimen that was determined to have the best balance of efficacy, safety, and compliance was hydroxychloroquine 400 mg twice daily on day one, followed by 200 mg twice daily on days two through five. Chloroquine and hydroxychloroquine are thought to act primarily by 1) altering endosomal pH and thus decreasing virus-cell fusion, and 2) interfering with terminal glycosylation of angiotensin-converting enzyme 2 (ACE-2) receptors, the putative receptor for the entry of SARS-CoV-2 into lower respiratory tract cells. These agents may also have immunomodulatory effects, especially given the use of hydroxychloroquine in rheumatologic disease. As chloroquine and hydroxychloroquine are generic and already on the market, they may be attractive alternatives to other agents that are currently being considered for COVID-19 management, but they deserve more rigorous study.





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